This invention relates to a new use of the low molecular weight thrombin inhibitor, melagatran.
Inflammation is a localised protective response elicited by injury or destruction of tissues, which serves to destroy, dilute or sequester both the injurious agent and the injured tissue.
Inflammation may result from physical trauma, infection, some chronic diseases (e.g. psoriasis and autoimmune diseases, such as rheumatoid arthritis) and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). A complex series of events may be involved, in which inflammatory mediators increase blood flow and dilation of local blood vessels, resulting in redness and heat, the exudation of fluids, often resulting in localised swelling, leukocytic migration into the inflamed area, and pain.
Current local and systemic treatments of inflammation, which treatments are employed typically when inflammation is an inappropriate response (e.g. in the treatment of autoimmune diseases), or is uncomfortable and/or inconvenient, include the administration of inter alia non-steroidal anti-inflammatory agents (NSAIDs), opioid analgesics and corticosteroids.
International patent application WO 94/29336 discloses a group of compounds that are useful as inhibitors of serine proteases, such as thrombin and/or kininogenases, such as kallikrein. The thrombin-inhibiting compounds are thus indicated as anticoagulants, and the kininogenase-inhibiting compounds as antiinflammatory agents.
One of the thrombin inhibiting compounds that is specifically disclosed in WO 94/29336 is HOOCxe2x80x94CH2xe2x80x94(R)Cgl-Aze-Pab-H, which is also known as melagatran (see Example 1 of WO 94/29336, and the list of abbreviations in this document). The use of melagatran in the inhibition of kininogenases, and therefore in the treatment of inflammation, is neither mentioned nor suggested.
We have now found, surprisingly, that melagatran elicits a notable antiinflammatory effect, for example as described below, and may thus be used to treat inflammation in preferably mammalian, and especially human, patients.
According to a first aspect of the invention there is provided the use of melagatran, or a pharmaceutically acceptable derivative or prodrug thereof, in the manufacture of a medicament for the treatment of inflammation.
The term xe2x80x9cinflammationxe2x80x9d will be understood by those skilled in the art to include any condition characterised by a localised protective response elicited by injury or destruction of tissues resulting from any of the causes mentioned hereinbefore, and which is manifest by heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with the inflammatory condition. The term will thus be understood to include inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, as well as all other forms of inflammation known to those skilled in the art.
Melagatran, and derivatives and prodrugs thereof, may thus be used in the direct treatment of inflammation resulting from injury, from viral or bacterial infection, or from a disease characterised by inflammation as one of its symptoms. Such diseases include autoimmune diseases, such as rheumatoid arthritis, psoriasis, allergy, asthma, rhinitis, pancreatitis, uticaria and inflammatory bowel syndrome.
However, melagatran, and derivatives and prodrugs thereof, are preferably used in the treatment of inflammation in patients with, or at risk of, a disease in which inhibition of thrombin is desired or required (see, for example, those listed in international patent application WO 97/23499), such as a thrombotic disease. Although the treatment may be of patients whose inflammatory and thrombotic diseases are unrelated, we prefer that the treatment is of a patient with a thrombotic disease in which inflammation plays a part in triggering coagulation. For example, inflammation may arise in blood vessel walls due to the presence and/or the action of microbes and/or the agents released thereby, physical damage, atheroscelorotic lesions and other inflammation-inducing agents. It is preferred that melagatran, and derivatives and prodrugs thereof, are used in the treatment of inflammation in patients having, or at risk of having, a thrombus.
For the avoidance of doubt, as used herein, the term xe2x80x9ctreatmentxe2x80x9d includes the therapeutic and/or prophylactic treatment of inflammation.
xe2x80x9cPharmaceutically acceptable derivativesxe2x80x9d includes salts (e.g. pharmaceutically acceptable non-toxic organic or inorganic acid addition salts) and solvates. The term xe2x80x9cprodrugxe2x80x9d of melagatran includes any compound that, following oral or parenteral administration, is metabolised in vivo to form melagatran (see, for example, international patent application WO 97/23499). Preferred prodrugs are those of the formula R1O2Cxe2x80x94CH2xe2x80x94(R)Cgl-Aze-Pab-OH (see the list of abbreviations in WO 97/23499), wherein R1 represents linear or branched C1-6 alkyl (e.g. C1-4 alkyl, especially methyl, propyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab.
Melagatran, and derivatives and prodrugs thereof, may be administered for systemic delivery to the site of inflammation, or may be administered for delivery directly (locally) to that site, using appropriate means of administration that are known to the skilled person.
Thus, in accordance with the invention, melagatran, and derivatives and prodrugs thereof, may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, topically, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the active ingredient in a pharmaceutically acceptable dosage form. Depending on the disorder, and the patient, to be treated, as well as the route of administration, the compositions may be administered at varying doses.
Preferred modes of delivery are systemic. For melagatran and derivatives thereof, preferred modes of administration are parenteral, more preferably intravenous, and especially subcutaneous. For prodrugs of melagatran, preferred modes of administration are oral.
In the therapeutic treatment of mammals, and especially humans, melagatran and derivatives and prodrugs thereof may be administered alone, but will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice. The preparation of is suitable formulations for use in administering melagatran, derivatives and prodrugs thereof is described in the literature, for example as described in inter alia international patent applications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO 97/39770, WO 97/45138, WO 98/16252, WO 99/27912 and WO 99/27913, the disclosures in which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques.
The amounts of melagatran, or derivative or prodrug thereof, in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
According to a further aspect of the invention there is provided a pharmaceutical formulation for use in the treatment of inflammation comprising an effective amount of melagatran or a pharmaceutically acceptable derivative or prodrug thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Melagatran, and derivatives and prodrugs thereof, may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAIDs, corticosteroids and analgesics), and/or other therapeutic agents that are useful in the treatment of a disease characterised by inflammation as one of its symptoms. Melagatran, and derivatives and prodrugs thereof, may also be combined with other therapeutic agents which, when administered, are known to give rise to inflammation as a side-effect. When melagatran, and derivatives and prodrugs thereof, are xe2x80x9ccombinedxe2x80x9d with other therapeutic agents in this way, the active ingredients may be administered together in the same formulation, or administered separately (simultaneously or sequentially) in different formulations.
Suitable doses of melagatran, prodrugs and derivatives thereof, in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients are those which give a mean plasma concentration in the range 0.01 to 5 xcexcmol/L. In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
The skilled person will also appreciate that melagatran, or a derivative or prodrug thereof, may be administered in an appropriate dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
According to a further aspect of the invention there is provided a method of treating inflammation which comprises administering a therapeutically effective amount of melagatran, or a pharmaceutically acceptable derivative or prodrug thereof, to a patient in need of such treatment.
The use and method described herein may have the advantage that, in the treatment of inflammation, melagatran and derivatives and prodrugs thereof may not possess disadvantages of known antiinflammatory agents. The use and method described herein may also have the advantage that melagatran and derivatives and prodrugs thereof may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art for the treatment of inflammation.